Nextgen Dissection of the Genomic Basis of Kidney Development

肾脏发育基因组基础的 Nextgen 剖析

• 批准号: 8047815
• 负责人: Bruce J Aronow
• 金额: $ 181.31万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047815
• 关键词: Antibodies; Atlases; Automobile Driving; Binding Sites; Cells; Chromatin; Code; DNA; Data; Disease; Dissection; Dissociation; Distal; Elements; Endothelial Cells; Engineering; Epitopes; Event; Gene Expression; Genes; Genetic; Genetic Programming; Genomics; Growth Factor Receptors; Hand; Henle' s loop; Kidney; Lead; Measures; Mesenchyme; Messenger RNA; Metanephric Diverticulum; Methods; MicroRNAs; Molecular Mechanisms of Action; Molecular Profiling; Mus; Mutation; Pattern; Play; Process; Promoter Regions; Proteins; RNA Processing; RNA Splicing; Renin; Resources; Role; Sequence Analysis; Series; Shapes; Stem cells; Stromal Cells; Technology; Time; Transcript; Transcription factor genes; Transgenic Mice; Transgenic Organisms; Vesicle; Work; analog; base; cell type; chromatin immunoprecipitation; crosslink; in vivo; interest; laser capture microdissection; mesangial cell; molecular marker; mutant; nephrogenesis; novel; podocyte; programs; promoter; repaired; success; transcription factor

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to conduct a NexGen RNA-Seq based dissection of the gene expression program driving kidney development. The central thesis is straightforward. We propose to define, in a sensitive and quantitative manner, all of the sets of genes active in each critical cell type of the developing kidney. An atlas will be generated, comprehensive in character, including microRNAs as well as more orthodox coding mRNAs, and providing detailed analyses of alternative RNA processing events. The end result will be an essential resource, describing the analog gene expression code that defines and drives each compartment of the developing kidney. This resource will identify all of the growth factors, receptors and transcription factors expressed in each cell type. It will establish a set of novel cell type specific molecular markers, useful in mutant analyses. In addition it will provide a standard baseline for the global analysis of changes in gene expression patterns occurring as a result of mutation or disease. In addition we propose to use a Chip-Seq approach to discover the direct downstream targets of the transcription factors Hoxa11, Lhx1 and Six2. Each has been shown to play an important role in kidney development, and by identifying their direct downstream targets we will gain a better view of their precise roles in the process of nephrogenesis. PUBLIC HEALTH RELEVANCE: The proposed work would use the latest revolutionary sequencing technology to characterize all of the gene activities in the many different cell types of the developing kidney. This would lead to a much deeper understanding of the genetic program that drives the process of making a kidney, which in turn will in time help us better understand how to repair kidneys that have been damaged by disease.

描述（由申请人提供）：本提案的长期目标是对驱动肾脏发育的基因表达程序进行基于NexGen RNA-Seq的解剖。中心论点是直截了当的。我们建议以灵敏和定量的方式定义发育中肾脏的每个关键细胞类型中的所有基因组。将生成一个图谱，其特征全面，包括microRNA以及更正统的编码mRNA，并提供替代RNA加工事件的详细分析。最终结果将是一个重要的资源，描述了定义和驱动发育中肾脏每个隔室的模拟基因表达代码。 这个资源将确定所有的生长因子，受体和转录因子在每种细胞类型中表达。它将建立一套新的细胞类型特异性分子标记，用于突变分析。此外，它将为全球分析因突变或疾病而发生的基因表达模式变化提供标准基线。 此外，我们建议使用Chip-Seq方法来发现转录因子Hoxa 11，Lhx 1和Six 2的直接下游靶标。每一个都被证明在肾脏发育中起着重要的作用，通过识别它们的直接下游靶点，我们将更好地了解它们在肾脏发生过程中的确切作用。 公共卫生相关性：这项拟议中的工作将使用最新的革命性测序技术来表征发育中肾脏的许多不同细胞类型中的所有基因活动。这将导致对驱动肾脏形成过程的遗传程序有更深入的了解，这反过来又将帮助我们更好地了解如何修复因疾病而受损的肾脏。

项目成果

RNA-Seq defines novel genes, RNA processing patterns and enhancer maps for the early stages of nephrogenesis: Hox supergenes.

• DOI: 10.1016/j.ydbio.2012.05.030
• 发表时间: 2012-08-01
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Brunskill EW;Potter SS
• 通讯作者: Potter SS